rs17612852 — HLA-DQA1 HLA-DQA1 Peanut Allergy Tag SNP

HLA-DQA1 rs17612852 — The Peanut Allergy Haplotype Tag That Switches Sides

Buried in the most complex region of the human genome — the HLA class II locus¹¹ HLA class II locus
Human Leukocyte Antigen class II genes on chromosome 6p21 encode the antigen-presenting molecules that determine which proteins the immune system tolerates and which it attacks — lies a variant with a paradoxical property: the same genetic signal that increases peanut allergy risk when peanut is avoided promotes powerful immune protection when peanut is consumed early. rs17612852 is an intronic variant in HLA-DQA1 at chromosome 6:32,652,795 (GRCh38), in strong linkage disequilibrium (D′=0.99, r²=0.65) with the HLA-DQA1*01:02 haplotype²² HLA-DQA1*01:02 haplotype
A specific variant of the alpha chain of the HLA-DQ antigen-presenting molecule, determined by classical HLA typing. Because G and A are the two alleles at this position and the G allele nearly always travels with HLA-DQA1*01:02, rs17612852 functions as a convenient tag SNP — a genotyping proxy for a classical HLA haplotype that is expensive and technically demanding to type directly.

The Mechanism

HLA-DQ molecules are heterodimers on the surface of antigen-presenting cells³³ antigen-presenting cells
Dendritic cells, B cells, and macrophages that process proteins into peptide fragments and display them to naïve CD4+ T cells, shaping whether tolerance or immune activation follows. The specific DQ alpha chain encoded by DQA1*01:02 has a binding groove that presents peanut protein peptides — particularly from Ara h 2⁴⁴ Ara h 2
The dominant IgE target in clinical peanut allergy; a storage protein in the peanut seed that drives most anaphylactic reactions — with high efficiency to naïve T cells.

Crucially, rs17612852 is not just a passive marker of the haplotype. It is the primary cis-eQTL⁵⁵ cis-eQTL
A variant that controls expression of a nearby gene in cis — on the same chromosome segment for HLA-DQB1 in CD4+ T cells: each additional copy of the G minor allele drives significantly higher HLA-DQB1 RNA levels (p=8.34×10⁻¹³), increasing the amount of HLA-DQ molecule on the antigen-presenting cell surface. The direction of immune outcome this creates — tolerance or allergy — depends entirely on whether peanut protein arrives via the gut route (oral, tolerogenic) or the skin/airway route (sensitising)⁶⁶ gut route (oral, tolerogenic) or the skin/airway route (sensitising)
The route of first antigen encounter decisively shapes T cell polarisation; gut mucosal exposure favours Treg and IgG4; cutaneous exposure favours Th2 and IgE. More HLA-DQ expression on antigen-presenting cells in the gut amplifies the tolerogenic signal; the same upregulation in sensitised individuals amplifies the allergic response.

The Evidence

The Hong et al. 2015 GWAS⁷⁷ Hong et al. 2015 GWAS
Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nature Communications, 2015; 2,197 participants of European ancestry from the Chicago Food Allergy Study was the first genome-wide study of peanut allergy and identified the HLA-DQ/DR region at 6p21.32 as the dominant susceptibility locus, with the lead SNPs rs9275596 and rs7192 tagging the same HLA-DQA1*01:02 haplotype that rs17612852 also marks. The Asai et al. 2018 Canadian GWAS⁸⁸ Asai et al. 2018 Canadian GWAS
A Canadian genome-wide association study and meta-analysis confirm HLA as a risk factor for peanut allergy independent of asthma. JACI, 2018; >7,800 subjects across 8 studies confirmed this locus as the primary genetic signal for peanut allergy and identified rs17612852 specifically among HLA SNPs significantly associated with peanut allergy, particularly in individuals with mild reaction history.

The mechanistic insight came from the LEAP trial. Kanchan et al. 2026⁹⁹ Kanchan et al. 2026
Genetic Determinants of Peanut-Specific IgG4 Levels in the Context of Sustained Oral Peanut Exposure in the LEAP Study. Immunology, 2026; 267 LEAP peanut-consumption group participants conducted a GWAS of peanut-specific IgG4 in participants who consumed peanut throughout the trial. rs17612852 showed the strongest genome-wide signal (p=5.80×10⁻⁷) for total peanut-specific IgG4, with a component-specific association for Ara h 2 IgG4 (p=7.28×10⁻⁶, beta=0.324). Critically, no association was observed in the peanut-avoidance group — the relationship between the G allele and IgG4 exists only when peanut is regularly consumed.

Dantzer et al. 2022¹⁰¹⁰ Dantzer et al. 2022
HLA-associated outcomes in peanut OIT trials. Frontiers Immunology, 2022; IMPACT (ages 12–48 months) and POISED (ages 7–55 years) OIT trials demonstrated that HLA-DQA1*01:02 carriers — a group overwhelmingly identified by their G allele at rs17612852 — show substantially superior outcomes in peanut oral immunotherapy: desensitization in 93% vs 78% (IMPACT) and sustained unresponsiveness in 52% vs 31% (POISED). The protective immune benefit weakens significantly with age — younger children show the strongest effect, consistent with the critical window for immune tolerance induction.

Practical Actions

The most important clinical application of this variant is early-life peanut introduction. For G allele carriers whose infants are at elevated risk for peanut allergy (eczema, egg allergy), early peanut introduction (LEAP protocol: before 11 months) completely overrides the genetic susceptibility and channels the DQA1*01:02 haplotype toward high IgG4 protection rather than IgE sensitisation. The G allele that raises allergy risk under avoidance conditions actively promotes the strongest protective response under consumption conditions.

For individuals who have already developed peanut allergy, G allele status predicts superior response to oral immunotherapy across multiple independent trials — making this genotype a useful predictor of OIT candidacy and expected outcomes.

Interactions

rs17612852 operates within the broader HLA class II haplotype architecture centred on chromosome 6p21. Its closest functional interaction is with rs9275596, the intergenic tag SNP between HLA-DQB1 and HLA-DQA2 that also tags HLA-DQA1*01:02 and was the top GWAS hit in the Hong 2015 study. Both SNPs are in LD with the same DQA1*01:02 haplotype and have overlapping but distinct LD relationships; carrying risk alleles at both positions provides the strongest haplotype resolution.

The interaction with rs2187668 (tagging HLA-DQ2.5, associated with celiac disease and type 1 diabetes) is architecturally important: DQA1*01:02 and DQ2.5 are generally on different haplotypes, so compound heterozygotes carrying the G allele at rs17612852 and the A allele at rs2187668 carry risk across distinct HLA-mediated immune-condition pathways simultaneously. This combination is documented in the compound actions in this database.